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Biomedical subjects

T van der Poll

Publications and source records attributed to T van der Poll.

At least 73 records · Page 4Linked to original sources
PubMed2000

A single oral dose of thalidomide enhances the capacity of lymphocytes to secrete gamma interferon in healthy humans.

Thalidomide is increasingly being used as adjuvant therapy for patients with mycobacterial and human immunodeficiency virus (HIV) infections. The T-helper (Th)1 cytokine-Th2 cytokine balance critically determines the outcomes of these diseases. To obtain insight into the effect of thalidomide on the capacity of lymphocytes to produce Th1 and Th2 cytokines, six healthy volunteers received an oral dose (400 mg) of thalidomide. Before and at 3, 6, and 24 h after ingestion of thalidomide, peripheral blood mononuclear cells (PBMCs) were isolated and stimulated for 24 h with the T-cell stimulant staphylococcal enterotoxin B (SEB) or anti-CD3/CD28. In all six volunteers ingestion of thalidomide was associated with enhanced SEB- and anti-CD3/CD28-induced production of the Th1 cytokine gamma interferon (P < 0.05) and a decrease in the level of anti-CD3/CD28-induced interleukin-5 (IL-5) production (P < 0.05). The levels of IL-2 (Th1) and IL-4 (Th2) released remained unchanged. These changes were accompanied by an increase in the amount of IL-12p40 released by the PBMCs 6 h after ingestion of thalidomide (P < 0.05). Thus, a single oral dose of thalidomide causes a Th1-type response in healthy humans. This finding offers a potential explanation for the positive effect of thalidomide in patients with mycobacterial and HIV infections.

Adult↗
PubMed2000

Interleukin-1 receptor type I gene-deficient mice are less susceptible to Staphylococcus epidermidis biomaterial-associated infection than are wild-type mice.

Elevated concentrations of interleukin-1 (IL-1) were found in tissue surrounding biomaterials infected with Staphylococcus epidermidis. To determine the role of IL-1 in biomaterial-associated infection (BAI), IL-1 receptor type I-deficient (IL-1R(-/-)) and wild-type mice received subcutaneous implants of silicon elastomer (SE) or polyvinylpyrrolidone-grafted SE (SEpvp), combined with an injection of 10(6) CFU of S. epidermidis or sterile saline. Neither mouse strain was susceptible to BAI around SE. IL-1R(-/-) mice with SEpvp implants had a no abscess formation and a reduced susceptibility to persistent S. epidermidis infection. The normal foreign body response, characterized by giant-cell formation and encapsulation, was delayed around SEpvp in wild-type mice but not in IL-1R(-/-) mice. This coincided with enhanced local IL-4 production in IL-1R(-/-) mice. These data suggest that inhibition of local IL-1 activity may be beneficial for the outcome of BAI.

Animals↗
PubMed2000

The CXC chemokines gamma interferon (IFN-gamma)-inducible protein 10 and monokine induced by IFN-gamma are released during severe melioidosis.

Gamma interferon (IFN-gamma)-inducible protein 10 (IP-10) and monokine induced by IFN-gamma (Mig) are related CXC chemokines which bind to the CXCR3 receptor and specifically target activated T lymphocytes and natural killer (NK) cells. The production of IP-10 and Mig by various cell types in vitro is strongly dependent on IFN-gamma. To determine whether IP-10 and Mig are released during bacterial infection in humans, we measured plasma levels of IP-10 and Mig in patients with melioidosis, a severe gram-negative infection caused by Burkholderia pseudomallei. IP-10 and Mig were markedly elevated in patients with melioidosis on admission, particularly in blood culture-positive patients, and remained elevated during the 72-h study period. Levels of IP-10 and Mig showed a positive correlation with IFN-gamma concentrations and also correlated with clinical outcome. In whole blood stimulated with heat-killed B. pseudomallei, neutralization of IFN-gamma and tumor necrosis factor alpha (TNF-alpha) partly attenuated IP-10 and Mig release, while anti-interleukin-12 (IL-12) and anti-IL-18 had a synergistic effect. Stimulation with other bacteria or endotoxin also induced strong secretion of IP-10 and Mig. These data suggest that IP-10 and Mig are part of the innate immune response to bacterial infection. IP-10 and Mig may contribute to host defense in Th1-mediated host defense during infections by attracting CXCR3(+) Th1 cells to the site of inflammation.

Adolescent↗
PubMed2000

Mycobacterial lipoarabinomannan induces an inflammatory response in the mouse lung. A role for interleukin-1.

Lipoarabinomannan (LAM), a cell wall component of Mycobacterium tuberculosis, induces the production of cytokines and chemokines in vitro. Interleukin-1 (IL-1) contributes to granuloma formation in tuberculosis (TB), and exerts effects via the IL-1 receptor type I (IL-1R). To determine the effects of LAM in the pulmonary compartment in vivo and to establish the role of endogenous IL-1 herein, normal and IL-1R deficient ((-/-)) mice were intranasally inoculated with LAM (50 microgram). In normal mice, LAM resulted in a neutrophilic cell influx into the bronchoalveolar lavage fluid (BALF). LAM also induced increases in the lung concentrations of macrophage inflammatory protein-2 (MIP-2), keratinocyte (KC), tumor necrosis factor-alpha (TNF-alpha), IL-1alpha, and IL-1beta. IL-1R(-/-) mice had less influx of granulocytes in their BALF than wild-type mice. Also, lung TNF-alpha levels were lower in IL-1R(-/-) mice. LAM may be an important stimulator of innate immunity in infection with M. tuberculosis via mechanisms that involve endogenous IL-1 activity.

Animals↗
PubMed2000

Characterization of transgenic mice that secrete functional human protein C inhibitor into the circulation.

Protein C inhibitor (PCI) is a heparin binding serine protease inhibitor in plasma, which exerts procoagulant activity by inhibiting thrombomodulin-bound thrombin or activated protein C (APC). Since the role of PCI in vivo is largely unknown we generated genetically modified mice with expression of human PCI mRNA in hepatocytes only. Three transgenic lines have been characterized. Transgenic mice did not show gross developmental abnormalities. Two lines showed a pericentral and one line showed a periportal expression pattern of human PCI mRNA in the liver. Genetically modified mice secreted a functional transgenic protein into the circulation (3-5 microg/ml plasma in heterozygous mice and 10 microg/ml in homozygous mice), which inhibited human APC activity in the presence of heparin. Interestingly, transgenic mice in which human PCI was expressed periportally in the liver had the highest specific activity. Endogenous mouse PCI mRNA could only be detected in the male and female reproductive system, but not in the liver, indicating that endogenous PCI levels in the circulation are low or even absent in mice. These results demonstrate that the human PCI transgenic mice are a suitable model for studying the in vivo role of PCI in blood coagulation.

Animals↗
PubMed1999

The effect of a metalloproteinase inhibitor (GI5402) on tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha receptors during human endotoxemia.

Tumor necrosis factor-alpha (TNF-alpha) is released from the cell surface by cleavage of pro-TNF-alpha by metalloproteinases (MPs). In cell cultures, inhibition of MPs has been found not only to reduce the release of TNF-alpha, but also to enhance the surface expression of TNF-alpha and TNF-alpha receptors, which might lead to a proinflammatory effect. To determine the effect of MP inhibition during inflammation in humans, 7 healthy subjects were studied after intravenous injection of lipopolysaccharide (LPS; 4 ng/kg) preceded (-20 minutes) by an oral dose of the MP inhibitor GI5402 (100 mg) or matching placebo. GI5402 strongly reduced LPS-induced TNF-alpha release (P <.001), but did not influence the increase in monocyte-bound TNF-alpha. In addition, GI5402 attenuated the rise in plasma-soluble TNF-alpha receptors types I and II after LPS injection (both P <.001), but did not change the LPS-induced decreases in granulocyte and monocyte TNF-alpha receptor expression. These data suggest that MP inhibitors may be useful as a treatment modality in diseases in which excessive production of TNF-alpha is considered to play an important role. Furthermore, unlike in vitro, no evidence has been found in vivo with MP inhibition for a potential proinflammatory effect due to increases in membrane-bound TNF-alpha and TNF-alpha receptor number.

Adult↗
PubMed1999

Mice without phosphatidylcholine transfer protein have no defects in the secretion of phosphatidylcholine into bile or into lung airspaces.

Phosphatidylcholine transfer protein (Pc-tp) is a highly specific carrier of phosphatidylcholine (PC) without known function. Proposed functions include the supply of PC required for secretion into bile or lung air space (surfactant) and the facilitation of enzymatic reactions involving PC synthesis or breakdown. To test these functions, we generated knock-out mice unable to make Pc-tp. Remarkably, these mice are normal and have no defect in any of the postulated Pc-tp functions analyzed. The lipid content and composition of the bile, as well as lung surfactant secretion and composition, of Pc-tp (-/-) mice, is normal. The lack of a Pc-tp contribution to biliary lipid secretion is in agreement with our finding that Pc-tp is down-regulated in adult mouse liver: whereas Pc-tp is abundant in the liver of mouse pups, Pc-tp levels decrease > 10-fold around 2 wk after birth, when bile formation starts. In adult mice, Pc-tp levels are high only in epididymis, testis, kidney, and bone marrow-derived mast cells. Absence of Pc-tp in bone marrow-derived mast cells does not affect their lipid composition or PC synthesis and degradation. We discuss how PC might reach the canalicular membrane of the hepatocyte for secretion into the bile, if not by Pc-tp.

Amino Acid Sequence↗
PubMed1999

Cytokines and anticytokines in the pathogenesis of sepsis.

Clinical trials with anti-inflammatory agents in patients with sepsis are based on the assumption that excessive proinflammatory activity of the cytokine network negatively influences the outcome of severe bacterial infections. The failure of these trials to show clinical benefit, in conjunction with recent experimental data, raises doubt about the validity of this assumption. This article reevaluates the role of cytokines in the pathogenesis of sepsis and severe bacterial infections. The cytokine network is discussed as consisting of proinflammatory cytokines, antiinflammatory cytokines, and soluble inhibitors of proinflammatory cytokines.

Animals↗
PubMed1999

Activation of mononuclear cells by interleukin-12: an in vivo study in chimpanzees.

Interleukin (IL)-12 is considered a central regulator of host resistance against a variety of pathogens. Therefore, IL-12 has been advocated as a potential therapeutic agent in infections. To determine the in vivo effects of IL-12 on mononuclear cells involved in the host immune response, four chimpanzees received an intravenous injection of recombinant IL-12 (1 microgram/kg). IL-12 induced a sustained decrease in lymphocyte counts, with decreases in CD3+/CD4+ and CD3+/CD8+ cells, while monocyte counts showed a transient increase. IL-12 injection resulted in a shift toward a Th1-mediated immune response as indicated by increased interferon-gamma production during whole-blood stimulation, while not influencing IL-4 production. IL-12-induced activation of NK cells and phagocytes, as indicated by increased NK cell cytotoxicity and increased plasma levels of granzymes A and B and of chitotriosidase activity. These data support the hypothesis that IL-12 may serve as a useful therapeutic agent in infections where a cell-mediated response is protective.

Animals↗
PubMed1999

Interleukin-12 induces sustained activation of multiple host inflammatory mediator systems in chimpanzees.

To determine in vivo effects of interleukin (IL)-12 on host inflammatory mediator systems, 4 healthy chimpanzees received recombinant human IL-12 (1 microg/kg) by intravenous injection. IL-12 induced increases in plasma concentrations of IL-15, IL-18, and interferon-gamma (IFN-gamma), plus a marked antiinflammatory cytokine response (IL-10, soluble tumor necrosis factor [TNF] receptors, IL-1 receptor antagonist) and secretion of alpha-chemokines (IL-8, IFN-gamma-inducible protein 10) and beta-chemokines (monocyte chemoattractant protein-1, macrophage inflammatory protein-1beta). In addition, IL-12 elicited neutrophilic leukocytosis, neutrophil degranulation (elastase-alpha1-antitrypsin complexes), coagulation activation (F1 + 2 prothrombin fragment, thrombin-antithrombin III complexes), and fibrinolytic activation (tissue-type plasminogen activator, plasmin-alpha2-antiplasmin complexes). IL-12-induced activation of multiple host mediator systems was found only after 8-24 h, remained detectable until the end of the 48-h observation period, and occurred in the absence of detectable TNF and IL-1beta. These data may contribute to understanding the role of IL-12 in the pathogenesis of sepsis syndrome and the toxicity found after repeated injections of IL-12.

Animals↗
PubMed1999

Elevated plasma concentrations of interferon (IFN)-gamma and the IFN-gamma-inducing cytokines interleukin (IL)-18, IL-12, and IL-15 in severe melioidosis.

Interferon (IFN)-gamma plays an important role in the pathogenesis of sepsis. Production of IFN-gamma is stimulated by synergistic effects of interleukin (IL)-18, IL-12, and IL-15. To investigate the regulation of IFN-gamma production during severe gram-negative infection, the plasma concentrations of IFN-gamma, IL-18, IL-12, and IL-15 were measured in 83 patients with suspected melioidosis. The diagnosis was confirmed in 62 patients, 31 of whom had blood cultures positive for Burkholderia pseudomallei, of whom 12 died. Compared with healthy controls, patients had elevated levels of IFN-gamma, IL-18, IL-12p40, and IL-15 on admission, with significantly higher levels in blood culture-positive patients, and these levels remained elevated during the 72-h study period. In whole blood stimulated with heat-killed B. pseudomallei, anti-IL-12 had a stronger inhibitory effect than anti-IL-18 and anti-IL-15 on IFN-gamma production. This effect of anti-IL-12 was further enhanced by anti-IL-18. These data suggest that during gram-negative sepsis, IFN-gamma production is controlled at least in part by endogenous IL-18, IL-12, and IL-15.

Adolescent↗
PubMed1999

Divergent roles of tumor necrosis factor and platelet-activating factor in endotoxin-induced release of monocyte chemoattractant protein 1 and macrophage inflammatory protein 1beta in chimpanzees.

A platelet-activating factor receptor antagonist reduced the release of macrophage inflammatory protein 1beta (MIP-1beta) during endotoxemia in chimpanzees but did not influence the secretion of monocyte chemoattractant protein 1 (MCP-1). Anti-tumor necrosis factor alpha monoclonal antibody completely prevented MCP-1 release and simultaneously enhanced the secretion of MIP-1beta. Levels of MIP-1beta and MCP-1 release were differentially regulated during endotoxemia.

Animals↗
PubMed1999

Elevated chemokine concentrations in sera of human immunodeficiency virus (HIV)-seropositive and HIV-seronegative patients with tuberculosis: a possible role for mycobacterial lipoarabinomannan.

Levels of interleukin 8 (IL-8), gamma interferon-inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1beta (MIP-1beta) were elevated in patients with tuberculosis. IP-10 and MCP-1 levels were higher in human immunodeficiency virus (HIV)-seropositive patients than in HIV-seronegative patients with tuberculosis. Lipoarabinomannan induced IL-8, MCP-1, and MIP-1beta in vitro, which was partly inhibited by anti-tumor necrosis factor antibody.

Chemokine CCL2↗
PubMed1999

Neutralization of TNF does not influence endotoxininduced changes in thyroid hormone metabolism in humans.

To determine the role of tumor necrosis factor (TNF) in endotoxin-induced changes in plasma thyroid hormone and thyroid-stimulating hormone (TSH) concentrations, 24 healthy postabsorptive humans were studied on a control study day (n = 6), after infusion of a recombinant TNF receptor IgG fusion protein (TNFR:Fc; 6 mg/m2; n = 6) after intravenous injection of endotoxin (2 ng/kg; n = 6), or after administration of endotoxin with TNFR:Fc (n = 6). Administration of TNFR:Fc alone did not affect thyroid hormone or TSH levels when compared with the control day. Endotoxin induced a transient rise in plasma TNF activity (1.5 h: 219 +/- 42 pg/ml), which was completely prevented by TNFR:Fc (P < 0.05). After endotoxin administration, plasma L-thyroxine (T4), free T4, 3,5, 3'-triiodothyronine (T3), and TSH were lower and 3,3', 5'-triiodothyronine was higher than on the control day (all P < 0. 05). Coinfusion of TNFR:Fc with endotoxin did not influence these endotoxin-induced changes. Our results suggest that endogenous TNF does not play an important role in the alterations in plasma thyroid hormone and TSH concentrations induced by mild endotoxemia in healthy humans.

Adult↗
PubMed1998

[Immunology in clinical practice. VIII. Role of cytokines in the pathogenesis of bacterial infections].

Cytokines are small proteins that can be produced by many different cell types involved in inflammation. The cytokine network consists of pro-inflammatory cytokines, facilitating inflammation, and anti-inflammatory cytokines, reducing inflammation at least in part by inhibiting the production of pro-inflammatory cytokines. The production of cytokines is enhanced during bacterial infections. The balance between pro- and anti-inflammatory cytokines critically determines the outcome of infection. Excessive systemic release of pro-inflammatory cytokines such as tumour necrosis factor alpha and interleukin 1 may contribute to organ failure in patients with fulminant sepsis. On the other hand, the local action of pro-inflammatory cytokines, at the site of a compartmentalized infection, is required for an adequate host antibacterial defence. Therefore, neutralization of pro-inflammatory cytokines may benefit some patients with bacterial sepsis but harm others.

Bacterial Infections↗
PubMed1998

Peritoneal cytokine release after elective gastrointestinal surgery and postoperative complications.

BACKGROUND: Laparotomy is known to give rise to systemic and local cytokine release. In the present study we investigated the course of the peritoneal response of tumor necrosis factor alpha (TNFalpha), interleukin (IL)-6, and IL-10 after elective gastrointestinal surgery and studied the differences in local cytokine response in patients developing postoperative complications. METHODS: Twelve consecutive patients underwent pancreatoduodenectomy (n = 9) or biliary and gastric bypass (n = 3) for pancreatic carcinoma. Sampling (TNFalpha, IL-6, IL-10) of fluid from abdominal drains was performed at return to the recovery unit (T=0), and at 3, 6, 18, 30, 42, 54, 66, 78 hours. Systemic sampling was performed at T=0, 3, 6, 18, 42, 66 hours. Postoperative cytokine response in patients with and without postoperative complications was compared. RESULTS: In patients without postoperative complications, peritoneal TNFalpha and IL-10 levels decreased in time (P = 0.07 and P = 0.01, respectively), whereas IL-6 did not change significantly during sampling (P = 0.28). Systemic IL-6 and IL-10 levels decreased 10-fold within 66 hours (IL-6, P = 0.04; IL-10, P = 0.06). Four patients experienced postoperative complications. All 4 patients with complications showed a second rise in peritoneal TNFalpha levels preceding the complication. All 4 patients had positive bacterial drain cultures from the abdominal drain, following the TNFalpha rise. CONCLUSIONS: After elective abdominal surgery, cytokines are released into the abdominal cavity. Intra-abdominal complications are accompanied or preceded by a peritoneal TNFalpha rise. In patients after elective gastrointestinal surgery, monitoring of peritoneal TNFalpha might be helpful in the early detection of severe intra-abdominal complications.

Aged↗